Sleep and inflammation: partners in sickness and in health

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Abstract

The discovery of reciprocal connections between the central nervous system, sleep and the immune system has shown that sleep enhances immune defences and that afferent signals from immune cells promote sleep. One mechanism by which sleep is proposed to provide a survival advantage is in terms of supporting a neurally integrated immune system that might anticipate injury and infectious threats. However, in modern times, chronic social threats can drive the development of sleep disturbances in humans, which can contribute to the dysregulation of inflammatory and antiviral responses. In this Review, I describe our current understanding of the relationship between sleep dynamics and host defence mechanisms, with a focus on cytokine responses, the neuroendocrine and autonomic pathways that connect sleep with the immune system and the role of inflammatory peptides in the homeostatic regulation of sleep. Furthermore, I discuss the therapeutic potential of harnessing these reciprocal mechanisms of sleep–immune regulation to mitigate the risk of inflammatory and infectious diseases.

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Fig. 1: Putative pathways for the effects of acute challenge or stress on immune system involvement in sleep.
Fig. 2: Putative pathways linking chronic stress or inflammatory exposure to sleep disturbance and adverse outcomes.
Fig. 3: A model for the effects of sleep disturbance on the regulation of immune response gene programmes.

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Acknowledgements

The author acknowledges research support provided by the US National Institutes of Health (Grants R01AG051944, R01AG056424-01, R01AG026364, R01CA160245, R01AG057750 and R01CA207130).

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M.R.I. conceptualized and wrote this article.

Correspondence to Michael R. Irwin.

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Glossary

Insomnia

Difficulty initiating or maintaining sleep, early awakening, interrupted or non-restorative sleep, and associated impairments in daytime functioning, which must be present for at least 3 nights per week and last for 3 months or longer.

Slow wave sleep

(SWS). A stage of sleep, also known as deep sleep, that ischaracterized by synchronized electroencephalogram activity with the presence of slow waves, or delta wave activity. SWS is often viewed as a time of rest for neocortical neurons, in which the brain recovers from activities during the day.

Circadian timing

In animals and humans, the sleep–wake cycle, which influences physiological processes including immunity, as well as levels of behavioural arousal.

Sleep disturbance

For the purpose of this Review, a condition defined as insomnia complaints with daytime consequences, dissatisfaction with sleep quality or quantity, and/or insomnia disorder.

Electroencephalogram

(EEG). A measure that tracks the electrical activity of the brain; one use is to graphically represent stages of sleep, which are defined by differences in waveform shape, frequency and amplitude.

Electromyogram

(EMG). A measure that tracks the electrical activity of muscle; one use, together with the EEG, is to define stages of sleep, such as rapid eye movement sleep, in which there is low muscle tone or activity accompanied by random and rapid eye movements.

Spindles

Bursts of oscillatory electroencephalogram activity that occur during stage 2 sleep, caused by a peak of electrical activity in one area of the brain followed by a peak of electrical activity in an adjacent area of the brain.

K-Complexes

Large event waveforms of electroencephalogram activity that are considered to be a defining brainwave of stage 2 sleep. They are characterized by a brief negative peak of electrical activity, followed by a longer-duration positive complex and then another negative peak.

Hypothalamic–pituitary–adrenal axis

(HPA axis). A neuroendocrine system that links the hypothalamus, pituitary and adrenal glands and functions to regulate the immune system in response to circadian signalling, behavioural states such as sleep and peripheral inflammatory signals.

Sympathetic nervous system

(SNS). A component of the autonomic nervous system that comprises nerve fibres that innervate lymphoid tissues, as well as nearly all other body tissues. The SNS regulates immune cell traffic and immune responses during sleep and in response to stress through the release of noradrenaline.

Circadian oscillator

Also known as the circadian clock. Cycles of oscillation are determined by biochemical signals and synchronized by solar time to influence 24-hour circadian timing in animals and in humans.

Experimental sleep deprivation

Imposing a loss of sleep during the night, for either part of the night (in other words, partial night sleep deprivation) or for the entire night (in other words, total night sleep deprivation).

Rapid eye movement sleep

(REM sleep). A stage of sleep, also known as paradoxical sleep, that is characterized by desynchronized electroencephalogram activity in a manner similar to waking, accompanied by random and rapid movement of the eyes together with low muscle tone. REM sleep is viewed as the sleep period in which there is a propensity to dream.

IL-6 transignalling

The ability of IL-6 to form an agonistic complex with a soluble IL-6 receptor and thereby to activate cells that lack the membrane-bound IL-6 receptor, such as neural cells.

Stress-induced sleep

A sleep-like state described in invertebrate models, in which a period of behavioural quiescence follows exposure to conditions that induce cellular stress, including exposure to tissue damage or extremes of temperature.

Sleep duration

The amount of time spent asleep during the night, measured either by subjective report or objectively, using polysomnography or actigraphy. Short sleep duration is defined as less than the reference amount of 7 hours per night and is typically characterized as being less than 6 hours of sleep per night. Long sleep duration is typically characterized as being more than 8 hours of sleep per night.

Conspecifics

Other animals belonging to the same species.

Sleep continuity

The relative distribution of uninterrupted sleep, as opposed to wakefulness, during the night, as measured by sleep efficiency (time spent asleep as a percentage of the total time spent in bed) and wake time after sleep onset (the amount of time spent awake after turning off the lights and initiating sleep).

C-reactive protein

(CRP). An acute phase protein that is synthesized by the liver in response to the production of IL-6 by macrophages or T cells.

Glucocorticoids

Neuroendocrine hormones that belong to the steroid hormone class, which suppress inflammation and antiviral immune responses, in addition to having a role in the metabolism of protein, fat and glucose.

Glucocorticoid resistance

A state of decreased sensitivity to the anti-inflammatory effects of glucocorticoids, which can be caused by ongoing increases in inflammation as well as by a genetic predisposition.

Parasympathetic

A component of the autonomic nervous system that comprises nerve fibres that innervate visceral tissues to regulate actions of the body when it is at rest, mainly through release of the neurotransmitter acetylcholine.

Inflammageing

Increasing levels of systemic markers of inflammation during the usual ageing process.

Cellular senescence

The state of a cell in which it is no longer able to replicate, which is also characterized by increased release of inflammatory mediators.

Epigenetic age

An estimate of biological age given by evaluating changes in DNA methylation at particular genomic locations, which is found to be more predictive of mortality risk than is chronological age.

Sleep consolidation

A sleep pattern characterized by high levels of sleep efficiency and low levels of awakening or sleep interruption.

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